The preparation of 1-naphthol mixed ethers raises remarkable interest, since it regards, for example, the synthesis of duloxetine 1a ((+)-(S)—N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropanamine), whose hydrochloride salt is used as antidepressant. EP 273 658 discloses two methods for the preparation of duloxetine or of its precursor 1b:

A first procedure comprises the use of 1-naphthol 3a

and of compounds of formula 2.

in particular compound 2a in which X═N(CH3)2.
The ether bond in compounds 1a and 1b forms through Mitsunobu reaction, which consists in the treatment in a ether solvent, for example tetrahydrofuran, of compounds 3a and 2 with equimolecular amounts of triphenylphosphine and of an azodicarboxylic acid ester (typically the diisopropyl ester). In this way the ether bond forms with inversion of configuration, obtaining as by-products equimolecular amounts of triphenylphosphine oxide and diisopropyl hydrazodicarboxylate, whose separation from the desired ether is troublesome. The X substituent in compounds 2 can be, further to —N(CH3)2, any good leaving group susceptible of being substituted with a nitrogen function which allows to obtain (+)-duloxetine 1a. The Mitsunobu reaction with compound 2a proceeds in more than 24 h. The equimolar ratio of the two reagents (triphenylphosphine and azodicarboxylate) with respect to compounds 2 and 3a and the prolonged reaction times make this synthetic procedure not very profitable, even if it proceeds with inversion of configuration at the oxygen-bearing carbon in compounds 2.
A method for the synthesis of duloxetine 1a that is preferred to the one reported above envisages the use of 1-fluoronaphthalene 3b

and 2a as substrates. Compound 2a is converted to the corresponding alkoxide by treatment with a strong base, for example NaH; the alkoxide replaces the fluorine at position 1 of 3b, leading to 1b. The substitution reaction of the fluorine on the aromatic ring is a particular reaction which involves an ionic intermediate (Meisenheimer intermediate) and which occurs, according to the state of the art, in N,N-dimethylacetamide and dimethylsulfoxide. When NaH is used as the base in DMSO, a temperature of 60-70° C. must not be exceeded. In particular, according to EP 273 658, compound 1b is obtained from 3b and 2a in N,N-dimethylacetamide, by treatment of 2 with sodium hydride, at a temperature of 70° C., to produce the alkoxide, followed by addition of 1-fluoronaphthalene 3b in equimolecular amount, heating at 110° C. for 60 min. The desired product 1b is recovered as crystalline oxalate in 76% yield.